Molecular dynamics simulations of mixtures of the ceramide N-(tetracosanoyl)-sphingosine (NS), cholesterol, and a free fatty acid are performed to gain a molecular-level understanding of the structure of the lipids found in the stratum corneum layer of skin. A new coarse-grained model for cholesterol, developed using the multistate iterative Boltzmann inversion method, is compatible with previously developed coarse-grained forcefields for ceramide NS, free fatty acid, and water, and validated against atomistic simulations of these lipids using the CHARMM force field. Self-assembly simulations of multilayer structures using these coarse-grained force fields are performed, revealing that a large fraction of the ceramides adopt extended conformations, which cannot occur in the bilayer structures typically studied using simulation. Cholesterol fluidizes the membrane by promoting packing defects and it is observed that an increase in cholesterol content reduces the bilayer height, due to an increase in interdigitation of the C24 lipid tails, consistent with experimental observations. Through the use of a simple reverse-mapping procedure, a self-assembled coarse-grained multilayer system is used to construct an equivalent structure with atomistic resolution. Simulations of this atomistic structure are found to closely agree with experimentally derived neutron scattering length density profiles. Significant interlayer hydrogen bonding is observed in the inner layers of the atomistic multilayer structure that are not found in the outer layers in contact with water or in equivalent bilayer structures. These results identify several significant differences in the structure and hydrogen bonding of multilayer structures as compared to the more commonly studied bilayer systems, and, as such, highlight the importance of simulating multilayer structures for more accurate comparisons with experiment. These results also provide validation of the efficacy of the coarse-grained forcefields and the framework for multiscale simulation.
Multiscale Simulation Methods Using Coarse-grained Model